title: Novel regulatory action of ribosomal inactivation on epithelial Nod2-linked proinflammatory signals in two convergent ATF3-associated pathways.
abstract: In response to excessive nucleotide-binding oligomerization domain-containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Microbiology and Immunology, Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-870, Korea;
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Do
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.forename: Ki-Hyung
authors.initials: KH
authors.lastname: Kim
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Park
authors.forename: Chang Gyu
authors.initials: CG
authors.lastname: Oh
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012270:Ribosomes / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D056284:Histone Deacetylase 1